ISM1745

ISM1745 is a novel, orally bioavailable, MTA-cooperative small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), developed by Insilico Medicine for the treatment of MTAP-deleted cancers. MTAP deficiency, occurring in approximately 15% of human cancers, leads to the accumulation of methylthioadenosine (MTA), which competes with the methyl-donor S-adenosylmethionine (SAM) to partially inhibit PRMT5 activity. ISM1745 selectively binds to the PRMT5-MTA complex, a state prevalent in MTAP-deficient cells, thereby achieving high specificity for tumors while sparing MTAP-wild-type tissues. Preclinical studies demonstrate that ISM1745 potently inhibits symmetric dimethylarginine (SDMA) formation, induces apoptosis, and causes cell cycle arrest and DNA damage specifically in MTAP-deleted tumor models. It has shown robust anti-tumor efficacy in xenograft models and exhibits synergistic activity when combined with MAT2A inhibitors such as ISM3412.